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Vol. 12, 911–914, September 2003 Cancer Epidemiology, Biomarkers & Prevention 911 Short Communication The Interaction between Alcohol Consumption and GSTM1 Genotype on Polycyclic Aromatic Hydrocarbon-DNA Adduct Levels in Breast Tissue1 Andrew Rundle, Deliang Tang, LaVerne Mooney, Introduction 2 Surah Grumet, and Frederica Perera We have been investigating the genetic and lifestyle determi- Departments of Epidemiology [A. R.] and Environmental Health Sciences nants of PAH3-DNA adduct levels in breast tissue and the [D. T., L. M., S. G., F. P.], Mailman School of Public Health, Columbia association between increased levels and breast cancer case- University, New York, New York 10032 control status (1–3). When adduct levels in tumor tissue from cases were compared with adduct levels in benign tissue from controls, high adduct levels were associated with breast cancer Abstract case-control status (1). The GSTM1-null genotype was associ- We investigated the association between alcohol ated with increased adduct levels in tumor and nontumor tissue consumption, GSTM1 genotype, and polycyclic aromatic from cases, but it was not associated with adduct levels in hydrocarbon (PAH)-DNA adduct levels in breast tissue. benign tissue from controls (2). Case-control differences in Women referred for breast surgery were enrolled prior adduct levels were stronger among those with the GSTM1-null to surgery, responded to an interview, and gave a blood genotype. sample. Women diagnosed with ductal carcinoma in situ As in many other studies of breast cancer (4, 5), we found and invasive ductal or lobular cancer were defined as current alcohol consumption to be associated with breast cancer cases, and women with benign conditions without atypia case-control status (3). The mechanisms through which alcohol were defined as controls. Paraffin-embedded tumor and may cause breast cancer are unknown, although several have nontumor tissue from cases and benign tissue from been have proposed (4). We have hypothesized that alcohol controls were retrieved from the pathology samples. consumption may influence breast cancer risk by inducing and GSTM1 genotype status was determined by PCR using suppressing genes responsible for the metabolism of xenobiot- WBC DNA, and PAH-DNA adduct levels were measured ics (6, 7). Several animal and cell culture studies have demon- in breast tissue using immunohistochemistry. In tumor strated that ethanol exposure alters PAH metabolism and in- and nontumor tissue from cases, the GSTM1-null creases adduct formation (7–11). Recent experiments with genotype was associated with increased adduct levels MCF-10F breast cells have shown that cotreatment of cells with among current alcohol consumers but not among B[a]P and ethanol produced higher adduct levels than treatment nondrinkers. In nontumor tissue, the interaction between with B[a]P alone (7). Ethanol treatment was shown to reduce -the expression of GSTP1, and the authors attributed the in ؍ genotype and alcohol consumption was significant (P 0.02), but in tumor tissue, the interaction did not achieve creased adduct levels to ethanol-induced reductions in B[a]P In benign tissue from metabolism by GSTP1 (7). GSTP1 and GSTM1 both detoxify .(0.10 ؍ statistical significance (P controls, there was no association between genotype and PAH, creating water-soluble conjugates that are less reactive adducts, regardless of drinking status. Among subjects than the PAH diol-epoxide metabolites (12, 13). Thus, the GST with the null genotype who drank alcohol, adduct levels enzymes are thought to prevent reactive xenobiotics from dam- were significantly higher in tumor and nontumor tissue aging DNA (2, 12). Here we extend our earlier findings on from cases than in benign tissue from controls. These GSTM1 and show that the GSTM1 genotype is a stronger results indicate the presence of a novel gene-lifestyle predictor of PAH-DNA adduct levels in subjects who were interaction that influences PAH-DNA adduct levels in regular alcohol drinkers. breast tissue from cases but not controls. This apparent difference in PAH metabolism in response to alcohol may Materials and Methods be an important clue as to how alcohol influences breast cancer risk. Study Population. Patient recruitment has been described pre- viously in detail (1) and will only be described briefly here. From 1994 to 1998, women referred for breast surgery at Columbia-Presbyterian Medical Center were enrolled before surgery into a hospital-based case-control study. After informed Received 10/11/02; revised 5/5/03; accepted 5/22/03. consent had been obtained, during their preoperative tests, The costs of publication of this article were defrayed in part by the payment of patients took part in a structured interview covering established page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. reproductive breast cancer risk factors, active and passive 1 Supported by grants from the Department of the Army, United States Army smoking, dietary practices, other environmental and occupa- Medical Research and Materiel Command, DAMD17-94-J-4251, Noreen T. Hol- land Foundation, and National Cancer Institute Grant K07 CA92348. 2 To whom requests for reprints should be addressed, at Department of Environ- mental Health Sciences, Mailman School of Public Health, 60 Haven Avenue B1, New York, NY 10032. Phone: (212) 304-7280; Fax: (212) 544-1943; E-mail: 3 The abbreviations used are: PAH, polycyclic aromatic hydrocarbon; B[a]P, [email protected]. benzo(a)pyrene; GST, glutathione S-transferase; BBD, benign breast disease. Downloaded from cebp.aacrjournals.org on September 28, 2021. © 2003 American Association for Cancer Research. 912 Short Communication: Alcohol, GSTM1, and PAH-DNA Adducts in Breast Tissue Table 1 Adduct levels in breast tissue by current drinking status and GSTM1 genotype Current drinker Current non-drinker GSTM1 ϩ/ϩ, ϩ/Ϫ GSTM1 null GSTM1 ϩ/ϩ, ϩ/Ϫ GSTM1 null Tumor tissue 0.32 (1.72) n ϭ 25 0.59 (2.09) n ϭ 21a 0.35 (1.81) n ϭ 17 0.41 (1.67) n ϭ 19 Nontumor tissue 0.30 (1.55) n ϭ 25 0.51 (1.87) n ϭ 20b 0.38 (1.66) n ϭ 14 0.34 (1.64) n ϭ 17 Benign tissue 0.30 (1.45) n ϭ 9 0.34 (1.59) n ϭ 28c,d 0.34 (1.63) n ϭ 29 0.43 (1.55) n ϭ 15 a P ϭ 0.002 comparing adduct levels in tumor tissue by GSTM1 status. b P ϭ 0.003 comparing adduct levels in nontumor tissue by GSTM1 status. c In current drinkers who are GSTM1 null, adduct levels in tumor tissue are significantly higher than in benign tissue (P ϭ 0.002). d In current drinkers who are GSTM1 null, adduct levels in nontumor tissue are significantly higher than in benign tissue (P ϭ 0.01). tional exposures, and vitamin consumption. Patients whose analysis with the Cell Analysis System 200 microscope confirmed diagnosis was of ductal carcinoma in situ or invasive (Becton-Dickinson, San Jose, CA) running the Cell Measure- ductal or invasive lobular cancer were defined as cases. Patients ment software. A total of 50 cells (5 fields with 10 cells/field with rare tumors were not included because the small numbers scored) were measured on each tissue slide. Results are re- precluded analyses by histological type. Patients diagnosed ported in optical density units as described previously (15). with BBD or BBD with hyperplasia were classified as controls. Serial tissue slices from laboratory control breast tissue speci- Because patients were enrolled before diagnosis, matching of mens previously shown to have low and high staining for BBD controls to cases was not possible. BBD patients whose adducts were used as negative and positive control samples, diagnoses were other than these categories (e.g., BBD with respectively, and were run with every batch. As an additional atypia or lobular carcinoma in situ) were excluded from anal- negative control, in each batch, a laboratory control sample was ysis because of their elevated risk of future breast cancer. Breast run without the primary antibody. cancer patients seen at Columbia-Presbyterian Medical Center Statistical Methods. Absorbance data reflecting the extent of for follow-up surgery (e.g., mastectomy or re-excisions) after staining for PAH-DNA adducts was log (ln) transformed for an initial surgical biopsy at another hospital were excluded analyses to produce a more normal distribution. Results are from the study. Additional exclusion criteria included a prior reported as geometric means and geometric SDs (16). As part history of cancer at any site except basal skin cancer, current of the interview, subjects were asked to estimate the average pregnancy, recent bone fractures, or recent breastfeeding. The number of drinks they consumed per week during the 12 last two exclusion criteria were included because these factors months before the interview. Study subjects who responded that were thought to interfere with biomarkers used in other aspects they drank 0 drinks/week were classified as nonconsumers, and of this study. Study subjects responded to an interviewer- subjects who responded that on average they drank more than administered questionnaire and provided blood samples. Sam- 0 drinks/week were classified as regular current consumers of ples of paraffin-embedded tumor and nontumor tissue were alcohol. Subjects were cross-classified into four groups based retrieved from pathology blocks from cases, as were samples of on their GSTM1 genotype status and whether they were current benign tissue from BBD controls. Thus, two tissue samples, alcohol consumers. For each tissue type (tumor, nontumor, and tumor and nontumor, were available from cases, and one tissue benign), geometric mean adduct levels were calculated for each sample, benign, was available from the BBD controls. of the four alcohol consumption/genotype strata. t tests were A total of 119 cases and 108 BBD controls were enrolled used to determine whether GSTM1 status was associated with with a response rate of 76%.

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